Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to cancer. We have developed polymerase chain reaction-based methods to detect DNA sequence polymorphisms in four genes (glutathione transferase mu [GSTM1], debrisoquine hydroxylase [CYP2D6], aryl hydrocarbon hydroxylase [CYP1A1], n-acetyl transferase [NAT2]) associated with increased risk of cancer. There were significant differences in the frequency of the high risk GSTM1 genotype between Caucasian- American, African-American, Taiwanese, and Finnish populations. In an ongoing case-control study of bladder cancer (n=300), we found about 2-fold increased risk associated with the high risk GSTM1 genotype (OR 1.94 95% CI 1.19-3.2). Risk was highest among heavy cigarette smokers. These findings support a protective role for the GT mu enzyme in bladder cancer, particularly among heavy smokers. The results also suggest a possible relationship between ethnic genotype differences and ethnic tumor incidence differences. In addition, we have genotyped about 400 individuals in control and carcinogen-exposed populations and are analyzing how genotypes modulate the level of DNA damage (DNA adducts, mutation frequency, chromosome damage) in lymphocytes. Analysis of HPRT mutation frequency in smokers indicates that years of smoking, as well as current smoking, influences mutation damage.